Substituted 4-Biarylbutyric and 5-Biarylpentanoic Acid Derivatives as Matrix Metalloprotease Inhibitors are described in WO 96/15096, WO 97/43237, WO 97/43238, WO 97/43239, WO 97/43240, WO 97/43245, WO 97/43247 and WO 98/22436.
The matrix metalloproteases (matrix metalloendo-proteinases or MMPs) are a family of zinc endoproteinases which include, but are not limited to, interstitial collagenase (MMP-1), stromelysin (proteoglycanase, tansin, or MMP-3), gelatinase A (72 kDa-gelatinase or MMP-2), neutrophil collagenase (MMP-8), gelatinase B (95 kDa-gelatinase or MMP-9), macrophage elastase (MMP-12) and human collagenase 3 (MMP 13). These MMPs are secreted by a variety of cells including fibroblasts, chondrocytes, granulocytes and macrophages along with natural proteinatious inhibitors known as TIMPs (Tissue Inhibitor of MetalloProteinase).
All of these MMPs are capable of destroying a variety of connective tissue components of articular cartilage or basement membranes and a wide variety of extracellular matrix proteins. Each MMP is secreted as an inactive proenzyme which must be cleaved in a subsequent step before it is able to exert its own proteolytic activity. In addition to the matrix destroying effect, certain of these MMPs such as MMP-3 have been implemented as the in vivo activator for other MMPs such as MMP-1 and MMP-9 (A. Ho, H. Nagase, Arch. Biochem. Biophys., 267, 211-16 (1988); Y. Ogata, J. J. Enghild, H. Nagase, J. Biol. Chem., 267, 3581-84 (1992)). Thus, a cascade of proteolytic activity can be initiated by an excess of MMP-3. It follows that specific MMP-3 inhibitors should limit the activity of other MMPs that are not directly inhibited by such inhibitors.
In addition to its ability to degrade extracellular matrix proteins MMP-12 has also been shown to hydrolyse elastin (R. P. Mecham, T. J. Broekelmann, C. J. Fliszar, S. D. Shapiro, H. G. Welgus, R. M. Senior, J. Biol. Chem., 272, 18071-18076 (1997)). This activity is shared by other MMP enzymes, specifically MMP-2 and MMP-9.
It has also been reported that MMP-3, MMP-9 and MMP-12 can cleave and thereby inactivate the endogenous inhibitors of other proteinases such as elastase (P. G. Winyard, Z. Zhang, K. Chidwick, D. R. Blake, R. W. Carrell, G. Murphy, FEBS Letts., 279, 1, 91-94 (1991); T. J. Gronski, R. L. Martin, D. K. Kobayashi, B. C. Walsh, M. C. Holman, M. Huber, H. E. Van Wart, S. D. Shapiro, J. Biol. Chem., 272, 12189-12194 (1997)). Inhibitors of these MMP enzymes could thus influence the activity of other destructive proteinases by modifying the level of their endogenous inhibitors.
Macrophages from MMP-12 knock-out mice have a diminished capacity to degrade extracellular matrix components and to penetrate reconstituted basement membranes both in vitro and in vivo (J. M. Shipley, R. L. Wesselschmidt, D. K. Kobayashi, T. J. Ley, S. D. Shapiro, PNAS, 93, 3942-3946 (1996)). These results support the hypothesis that MMP-12 is required for macrophage mediated extracellular proteolysis and tissue invasion. In addition, MMP-12 knock-out mice do not develop emphysema or show elevated macrophage levels in response to smoking, whereas wild type mice do (R. D. Hautamaki, D. K. Kobayashi R. M. Senior, S. D. Shapiro, Science, 277, 2002-2004 (1997)). Therefore there is strong evidence supporting a role of M-12, secreted by activated alveolar macrophages, in the development of pulmonary emphysema In patients with emphysema and smoking subjects both MMP-1, -8, -9 and -12 released from alveolar macrophages and neutrophils are also implicated in the pathogenesis of COPD.
By means of their proteolytic activity, matrix metallo-proteases are involved in a number of respiratory diseases, e.g. the following:                asthma; chronic obstructive pulmonary disease including chronic bronchitis and emphysema; cystic fibrosis; bronchiectasis; adult respiratory distress syndrom (ARDS); allergic respiratory disease including allergic rhinitis; diseases linked to TNFα production including acute pulmonary fibrotic diseases, pulmonary sarcoidosis, silicosis, coal worker's pneumoconiosis, alveolar injury.        
Evidence for the involvement of matrix metalloproteases in various respiratory diseases is provided by the following references:
a)COPD,Finlay et al.Thorax 1997, 52, 502chronicAm. J. Resp. Crit Care Med. 1997,bronchitis156, 240and Cateldo et al.Am. J. Resp. Crit. Care Med. 1998,emphysema157, A 502Sedura et al.Am. J. Resp. Crit. Care Med. 1998,157, A 568Shapiro et al.J. Biol. Chem. 1993, 268, 23824Kostan et al.Am. J. Resp. Crit. Care Med. 1998,157, A 143RiccobonoEur. Resp. J. 1997, 10, 26Sb)bronchi-Sepper et al.Chest 1995, 107, 1641ectasisSepper et al.Eur. Resp. J. 1997, 10, 278Sc)cysticDelacourt et al.Am. J. Resp. Crit. Care Med. 1995,fibrosis152, A 764Power et al.Am. J. Resp. Crit. Care Med. 1994,150, 818d)asthmaShute et al.Int. Arch. Allergy Immunol. 1997,111Ohno et al.Am. J. Resp. Cell. Mol. Biol. 1997,16, 212Mantino et al.Am. J. Resp. Cell. Mol. Biol. 1997,17, 583Okada et al.Am. J. Resp. Cell. Mol. Biol. 1997,17, 519e)ARDSDelclaux et al.Am. J. Physiol. 1997,272, L442.
In addition to chronic lung diseases a number of other conditions are thought to be mediated by excess or undesired matrix-destroying metalloprotease activity or by an imbalance in the ratio of the MMPs to the TIMPs or through the action of the release of TNF.
MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteases such as the adamalysin family (or ADAMs) whose members include TNFα converting enzyme (TACE) and ADAM-10, which can cause the release of TNF from cells.